This proposal is designed to reflect the effects of cigarette smoking on cleft lip with or without cleft palate (CL(P)) development in mice. CL(P) has a multifactorial etiology with both genetic and environmental factors playing a role. It is well documented that infants born to mothers who smoke have decreased birth weights and there is epidemiological evidence that CL(P) incidence is increased. Most of the prenatal effects apparently result from embryonic and fetal hypoxia due to the carbon monoxide, (CO) present in the cigarette smoke. Maternal respiratory hypoxia is known to increase the incidence of CL(P) in CL/Fr and A/J mice. Further studies have demonstrated early breakdown of the invaginating placode suggesting that only brief exposures may be necessary. We now have direct evidence that CO in air at levels similar to that of cigarette smoke (sufficient to elevate blood carboxyhemoglobin levels to 16-18%, the upper end of the range for cigarette smokers) also increases the incidence of CL(P) in A/J mice. The incidence is approximately six times that of controls and appears to be greater than the incidence (3-4 times that of controls) for maternal respiratory hypoxia, 6-8 litters were used for each of the 3 groups. In this application, we propose to complete the study comparing the incidence of CL(P) resulting from respiratory CO (180 ppm in air) to that resulting from maternal respiratory hypoxia (10% O2, 90% N2). The control group is subjected to normoxia (air: 22% O2, 90% N2). The peak sensitive period and minimum period of exposure for doubling the CL(P) incidence will be determined for CO. A dose response study for CO will then be conducted. Finally the developmental alterations resulting from CO administration and leading to CL(P) formation will studied by scanning EM and light microscopy.